A Low-Cost Handheld Impedimetric Biosensing System for Rapid Diagnostics of SARS-CoV-2 Infections.

Current laboratory diagnostic approaches for virus detection give reliable results, but they require a lengthy procedure, trained personnel, and expensive equipment and reagents; hence, they are not a suitable choice for home monitoring purposes. This paper addresses this challenge by developing a portable impedimetric biosensing system for the identification of COVID-19 patients. This sensing system has two main parts: a throwaway two-working electrode (2-WE) strip and a novel read-out circuit, specifically designed for simultaneous signal acquisition from both working electrodes. Highly reliable electrochemical signal tracking from multiplex immunosensors provides a potential for flexible and portable multi-biomarker detection. The electrodes' surfaces were functionalized with SARS-CoV-2 Nucleocapsid Antibody enabling the selective detection of Nucleocapsid protein (N-protein) along with self-validation in the clinical nasopharyngeal swab specimens. The proposed programmable highly sensitive impedance read-out system allows for a wide dynamic detection range, which makes the sensor capable of detecting N-protein concentrations between 0.116 and 10,000 pg/mL. This lightweight and economical read-out arrangement is an ideal prospect for being mass-produced, especially during urgent pandemic situations. Also, such an impedimetric sensing platform has the potential to be redesigned for targeting not only other infectious diseases but also other critical disorders.

Portable Sensing Devices for Detection of COVID-19: A Review.

The coronavirus pandemic is the most challenging incident that people have faced in recent years. Despite the time-consuming and expensive conventional methods, point-of-care diagnostics have a crucial role in deterrence, timely detection, and intensive care of the disease's progress. Hence, this detrimental health emergency persuaded researchers to accelerate the development of highly-scalable diagnostic devices to control the propagation of the virus even in the least developed countries. The strategies exploited for detecting COVID-19 stem from the already designed systems for studying other maladies, particularly viral infections. The present report reviews not only the novel advances in portable diagnostic devices for recognizing COVID-19, but also the previously existing biosensors for detecting other viruses. It discusses their adaptability for identifying surface proteins, whole viruses, viral genomes, host antibodies, and other biomarkers in biological samples. The prominence of different types of biosensors such as electrochemical, optical, and electrical for detecting low viral loads have been underlined. Thus, it is anticipated that this review will assist scientists who have embarked on a competition to come up with more efficient and marketable in-situ test kits for identifying the infection even in its incubation time without sample pretreatment. Finally, a conclusion is provided to highlight the importance of such an approach for monitoring people to combat the spread of such contagious diseases.

Electronic Sensing Platform (ESP) Based on Open-Gate Junction Field-Effect Transistor (OG-JFET) for Life Science Applications: Design, Modeling and Experimental Results.

This paper presents a new field-effect sensor called open-gate junction gate field-effect transistor (OG-JFET) for biosensing applications. The OG-JFET consists of a p-type channel on top of an n-type layer in which the p-type serves as the sensing conductive layer between two ohmic contacted sources and drain electrodes. The structure is novel as it is based on a junction field-effect transistor with a subtle difference in that the top gate (n-type contact) has been removed to open the space for introducing the biomaterial and solution. The channel can be controlled through a back gate, enabling the sensor's operation without a bulky electrode inside the solution. In this research, in order to demonstrate the sensor's functionality for chemical and biosensing, we tested OG-JFET with varying pH solutions, cell adhesion (human oral neutrophils), human exhalation, and DNA molecules. Moreover, the sensor was simulated with COMSOL Multiphysics to gain insight into the sensor operation and its ion-sensitive capability. The complete simulation procedures and the physics of pH modeling is presented here, being numerically solved in COMSOL Multiphysics software. The outcome of the current study puts forward OG-JFET as a new platform for biosensing applications.

5-Axis CNC Micromilling for Rapid, Cheap, and Background-Free NMR Microcoils.

The superior mass sensitivity of microcoil technology in nuclear magnetic resonance (NMR) spectroscopy provides potential for the analysis of extremely small-mass-limited samples such as eggs, cells, and tiny organisms. For optimal performance and efficiency, the size of the microcoil should be tailored to the size of the mass-limited sample of interest, which can be costly as mass-limited samples come in many shapes and sizes. Therefore, rapid and economic microcoil production methods are needed. One method with great potential is 5-axis computer numerical control (CNC) micromilling, commonly used in the jewelry industry. Most CNC milling machines are designed to process larger objects and commonly have a precision of >25 µm (making the machining of common spiral microcoils, for example, impossible). Here, a 5-axis MiRA6 CNC milling machine, specifically designed for the jewelry industry, with a 0.3 µm precision was used to produce working planar microcoils, microstrips, and novel microsensor designs, with some tested on the NMR in less than 24 h after the start of the design process. Sample wells could be built into the microsensor and could be machined at the same time as the sensors themselves, in some cases leaving a sheet of Teflon as thin as 10 µm between the sample and the sensor. This provides the freedom to produce a wide array of designs and demonstrates 5-axis CNC micromilling as a versatile tool for the rapid prototyping of NMR microsensors. This approach allowed the experimental optimization of a prototype microstrip for the analysis of two intact adult Daphnia magna organisms. In addition, a 3D volume slotted-tube resonator was produced that allowed for 2D 1H-13C NMR of D. magna neonates and exhibited 1H sensitivity (nLODω600 = 1.49 nmol s1/2) close to that of double strip lines, which themselves offer the best compromise between concentration and mass sensitivity published to date.

Biosensing based on field-effect transistors (FET): Recent progress and challenges.

The use of field-Effect-Transistor (FET) type biosensing arrangements has been highlighted by researchers in the field of early biomarker detection and drug screening. Their non-metalized gate dielectrics that are exposed to an electrolyte solution cover the semiconductor material and actively transduce the biological changes on the surface. The efficiency of these novel devices in detecting different biomolecular analytes in a real-time, highly precise, specific, and label-free manner has been validated by numerous research studies. Considerable progress has been attained in designing FET devices, especially for biomedical diagnosis and cell-based assays in the past few decades. The exceptional electronic properties, compactness, and scalability of these novel tools are very desirable for designing rapid, label-free, and mass detection of biomolecules. With the incorporation of nanotechnology, the performance of biosensors based on FET boosts significantly, particularly, employment of nanomaterials such as graphene, metal nanoparticles, single and multi-walled carbon nanotubes, nanorods, and nanowires. Besides, their commercial availability, and high-quality production on a large-scale, turn them to be one of the most preferred sensing and screening platforms. This review presents the basic structural setup and working principle of different types of FET devices. We also focused on the latest progression regarding the use of FET biosensors for the recognition of viruses such as, recently emerged COVID-19, Influenza, Hepatitis B Virus, protein biomarkers, nucleic acids, bacteria, cells, and various ions. Additionally, an outline of the development of FET sensors for investigations related to drug development and the cellular investigation is also presented. Some technical strategies for enhancing the sensitivity and selectivity of detection in these devices are addressed as well. However, there are still certain challenges which are remained unaddressed concerning the performance and clinical use of transistor-based point-of-care (POC) instruments; accordingly, expectations about their future improvement for biosensing and cellular studies are argued at the end of this review.

A silver(I) doped bud-like DNA nanostructure as a dual-functional nanolabel for voltammetric discrimination of methylated from unmethylated genes.

A small DNA structure, referred to as DNA nanobud (NB), was used for the first time to design a dual-functional nanolabel in order to recognize a particular oligonucleotide sequence, generate and amplify the electrochemical analytical signal. NBs containing numerous repetitive desired sequences were prepared through self-assembly of 8-h rolling circle amplification. Then, redox-active silver ions were loaded onto the NBs by over-night incubation with a solution of AgNO3. The incorporation of Ag+ into NBs was confirmed by field emission scanning electron microscopy, dynamic light scattering, UV-Vis spectroscopy, zeta potential measurements, and energy-dispersive X-ray spectroscopy. A DNA sandwich complex was created after hybridization of Ag+-NB with target sequence, which was captured by immobilized probe on a gold electrode. Cyclic voltammetry was applied to measure the redox signal of silver ions produced typically at a potential around 0.02 V vs. Ag/AgCl. The label can specifically discriminate fully methylated BMP3 gene from fully unmethylated bisulfate-converted part of the gene. The electrochemical signal produced by DNA sandwich complex of gold/probe/BMP3/Ag+-NB was linear toward BMP3 concentration from 100 pM to 100 nM. The method has a 100 pM BMP3 detection limit. Conceivably, this nanolabel can be designed and modified such that it may also be used to detect other sequences with lower detection limits. Graphical abstract Ag+-NB as a new nanolabel for genosensing was formed by loading Ag+ on a spherical DNA nanostructure, nanobud (NB), synthesized by rolling circle amplification process. By using a gold electrode (AuE), Ag+-NB with numerous electroactive cations and binding sites can detect targets and generate amplified electrochemical signals.

Toward High Throughput Core-CBCM CMOS Capacitive Sensors for Life Science Applications: A Novel Current-Mode for High Dynamic Range Circuitry.

This paper proposes a novel charge-based Complementary Metal Oxide Semiconductor (CMOS) capacitive sensor for life science applications. Charge-based capacitance measurement (CBCM) has significantly attracted the attention of researchers for the design and implementation of high-precision CMOS capacitive biosensors. A conventional core-CBCM capacitive sensor consists of a capacitance-to-voltage converter (CVC), followed by a voltage-to-digital converter. In spite of their high accuracy and low complexity, their input dynamic range (IDR) limits the advantages of core-CBCM capacitive sensors for most biological applications, including cellular monitoring. In this paper, after a brief review of core-CBCM capacitive sensors, we address this challenge by proposing a new current-mode core-CBCM design. In this design, we combine CBCM and current-controlled oscillator (CCO) structures to improve the IDR of the capacitive readout circuit. Using a 0.18 µm CMOS process, we demonstrate and discuss the Cadence simulation results to demonstrate the high performance of the proposed circuitry. Based on these results, the proposed circuit offers an IDR ranging from 873 aF to 70 fF with a resolution of about 10 aF. This CMOS capacitive sensor with such a wide IDR can be employed for monitoring cellular and molecular activities that are suitable for biological research and clinical purposes.

An Improved Method for Magnetic Nanocarrier Drug Delivery across the Cell Membrane.

One of the crucial issues in the pharmacological field is developing new drug delivery systems. The main concern is to develop new methods for improving the drug delivery efficiencies such as low disruptions, precise control of the target of delivery and drug sustainability. Nowadays, there are many various methods for drug delivery systems. Carbon-based nanocarriers are a new efficient tool for translocating drug into the defined area or cells inside the body. These nanocarriers can be functionalized with proteins, peptides and used to transport their freight to cells or defined areas. Since functionalized carbon-based nanocarriers show low toxicity and high biocompatibility, they are used in many nanobiotechnology fields. In this study, different shapes of nanocarrier are investigated, and the suitable magnetic field, which is applied using MRI for the delivery of the nanocarrier, is proposed. In this research, based on the force required to cross the membrane and MD simulations, the optimal magnetic field profile is designed. This optimal magnetic force field is derived from the mathematical model of the system and magnetic particle dynamics inside the nanocarrier. The results of this paper illustrate the effects of the nanocarrier's shapes on the percentage of success in crossing the membrane and the optimal required magnetic field.

A Multidisciplinary Approach to High Throughput Nuclear Magnetic Resonance Spectroscopy.

Nuclear Magnetic Resonance (NMR) is a non-contact, powerful structure-elucidation technique for biochemical analysis. NMR spectroscopy is used extensively in a variety of life science applications including drug discovery. However, existing NMR technology is limited in that it cannot run a large number of experiments simultaneously in one unit. Recent advances in micro-fabrication technologies have attracted the attention of researchers to overcome these limitations and significantly accelerate the drug discovery process by developing the next generation of high-throughput NMR spectrometers using Complementary Metal Oxide Semiconductor (CMOS). In this paper, we examine this paradigm shift and explore new design strategies for the development of the next generation of high-throughput NMR spectrometers using CMOS technology. A CMOS NMR system consists of an array of high sensitivity micro-coils integrated with interfacing radio-frequency circuits on the same chip. Herein, we first discuss the key challenges and recent advances in the field of CMOS NMR technology, and then a new design strategy is put forward for the design and implementation of highly sensitive and high-throughput CMOS NMR spectrometers. We thereafter discuss the functionality and applicability of the proposed techniques by demonstrating the results. For microelectronic researchers starting to work in the field of CMOS NMR technology, this paper serves as a tutorial with comprehensive review of state-of-the-art technologies and their performance levels. Based on these levels, the CMOS NMR approach offers unique advantages for high resolution, time-sensitive and high-throughput bimolecular analysis required in a variety of life science applications including drug discovery.

An Optically-Transparent Aptamer-Based Detection System for Colon Cancer Applications Using Gold Nanoparticles Electrodeposited on Indium Tin Oxide.

In this paper, a label-free aptamer based detection system (apta-DS) was investigated for detecting colon cancer cells. For this purpose, we employed an aptamer specific to colon cancer cells like HCT116 expressing carcinoembryonic antigen (CEA) on their surfaces. Capture aptamers were covalently immobilized on the surface of gold nanoparticles (GNPs) through self-assembly monolayer of 11-mercaptoundecanoic acid (11-MUA) activated with EDC (1-Ethyl-3-[3-dimethylaminopropyl]carbodiimide)/N-hydroxysuccinimide (NHS). The cyclic voltammetry (CV) and chronopotentiometry (CP) methods were used for electrodeposition of GNPs on the surface of indium tin oxide (ITO). In this work, the CV method was also used to demonstrate the conjugation of GNPs and aptamers and identify the cancer cell capturing events. Additionally, Field Emission Scanning Electron Microscopy (FE-SEM) confirmed the deposition of GNPs on ITO and the immobilization of aptamer on the apta-DS. The electrodeposited GNPs played the role of nanoprobes for cancer cell targeting without losing the optical transparency of the ITO substrate. A conventional optical microscope also verified the detection of captured cancer cells. Based on this study's results relying on electrochemical and optical microscopic methods, the proposed apta-DS is reliable and high sensitive with a LOD equal to 6 cell/mL for colon cancer detection.

Wireless integrated biosensors for point-of-care diagnostic applications.

Recent advances in integrated biosensors, wireless communication and power harvesting techniques are enticing researchers into spawning a new breed of point-of-care (POC) diagnostic devices that have attracted significant interest from industry. Among these, it is the ones equipped with wireless capabilities that drew our attention in this review paper. Indeed, wireless POC devices offer a great advantage, that of the possibility of exerting continuous monitoring of biologically relevant parameters, metabolites and other bio-molecules, relevant to the management of various morbid diseases such as diabetes, brain cancer, ischemia, and Alzheimer's. In this review paper, we examine three major categories of miniaturized integrated devices, namely; the implantable Wireless Bio-Sensors (WBSs), the wearable WBSs and the handheld WBSs. In practice, despite the aforesaid progress made in developing wireless platforms, early detection of health imbalances remains a grand challenge from both the technological and the medical points of view. This paper addresses such challenges and reports the state-of-the-art in this interdisciplinary field.

Toward Epileptic Brain Region Detection Based on Magnetic Nanoparticle Patterning.

Resection of the epilepsy foci is the best treatment for more than 15% of epileptic patients or 50% of patients who are refractory to all forms of medical treatment. Accurate mapping of the locations of epileptic neuronal networks can result in the complete resection of epileptic foci. Even though currently electroencephalography is the best technique for mapping the epileptic focus, it cannot define the boundary of epilepsy that accurately. Herein we put forward a new accurate brain mapping technique using superparamagnetic nanoparticles (SPMNs). The main hypothesis in this new approach is the creation of super-paramagnetic aggregates in the epileptic foci due to high electrical and magnetic activities. These aggregates may improve tissue contrast of magnetic resonance imaging (MRI) that results in improving the resection of epileptic foci. In this paper, we present the mathematical models before discussing the simulation results. Furthermore, we mimic the aggregation of SPMNs in a weak magnetic field using a low-cost microfabricated device. Based on these results, the SPMNs may play a crucial role in diagnostic epilepsy and the subsequent treatment of this disease.

An Apta-Biosensor for Colon Cancer Diagnostics.

This paper reports the design and implementation of an aptasensor using a modified KCHA10a aptamer. This aptasensor consists of a functionalized electrodes using various materials including 11-mercaptoandecanoic acid (11-MUA) and modified KCHA10a aptamer. The HCT 116, HT 29 and HEp-2 cell lines are used in this study to demonstrate the functionality of aptasensor for colon cancer detection purposes. Flow cytometry, fluorescence microscopy and electrochemical cyclic voltammetry are used to verify the binding between the target cells and aptamer. The limit of detection (LOD) of this aptasensor is equal to seven cancer cells. Based on the experimental results, the proposed sensor can be employed for point-of-care cancer disease diagnostics.

A Multidisciplinary Approach toward CMOS Capacitive Sensor Array for Droplet Analysis.

This paper introduces an innovative method for the analysis of alcohol-water droplets on a CMOS capacitive sensor, leveraging the controlled thermal behavior of the droplets. Using this sensing method, the capacitive sensor measures the total time of evaporation (ToE), which can be influenced by the droplet volume, temperature, and chemical composition. We explored this sensing method by introducing binary mixtures of water and ethanol or methanol across a range of concentrations (0-100%, with 10% increments). The experimental results indicate that while the capacitive sensor is effective in measuring both the total ToE and dielectric properties, a higher dynamic range and resolution are observed in the former. Additionally, an array of sensing electrodes successfully monitors the droplet-sensor surface interaction. However practical considerations such as the creation of parasitic capacitance due to mismatch, arise from the large sensing area in the proposed capacitive sensors and other similar devices. In this paper, we discuss this non-ideality and propose a solution. Also, this paper showcases the benefits of utilizing a CMOS capacitive sensing method for accurately measuring ToE.

Emerging Field-Effect Transistor Biosensors for Life Science Applications.

Field-effect transistors (FETs) have gained significant interest and hold great potential as groundbreaking sensing technology in the fields of biosensing and life science research [...].

Design and Analysis of a Low-Voltage VCO: Reliability and Variability Performance.

This paper investigates an adaptive body biasing (ABB) circuit to improve the reliability and variability of a low-voltage inductor-capacitor (LC) voltage-controlled oscillator (VCO). The ABB circuit provides VCO resilience to process variability and reliability variation through the threshold voltage adjustment of VCO's transistors. Analytical equations considering the body bias effect are derived for the most important relations of the VCO and then the performance is verified using the post-layout simulation results. Under a 0.16% threshold voltage shift, the sensitivity of the normalized phase noise and transconductance of the VCO with the ABB circuit compared to the constant body bias (CBB) decreases by around 8.4 times and 3.1 times, respectively. Also, the sensitivity of the normalized phase noise and transconductance of the proposed VCO under 0.16% mobility variations decreases by around 1.5 times and 1.7 times compared to the CBB, respectively. The robustness of the VCO is also examined using process variation analysis through Monte Carlo and corner case simulations. The post-layout results in the 180 nm CMOS process indicate that the proposed VCO draws a power consumption of only 398 µW from a 0.6 V supply when the VCO frequency is 2.4 GHz. It achieves a phase noise of -123.19 dBc/Hz at a 1 MHz offset and provides a figure of merit (FoM) of -194.82 dBc/Hz.

CoVSense: Ultrasensitive Nucleocapsid Antigen Immunosensor for Rapid Clinical Detection of Wildtype and Variant SARS-CoV-2.

The widespread accessibility of commercial/clinically-viable electrochemical diagnostic systems for rapid quantification of viral proteins demands translational/preclinical investigations. Here, Covid-Sense (CoVSense) antigen testing platform; an all-in-one electrochemical nano-immunosensor for sample-to-result, self-validated, and accurate quantification of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid (N)-proteins in clinical examinations is developed. The platform's sensing strips benefit from a highly-sensitive, nanostructured surface, created through the incorporation of carboxyl-functionalized graphene nanosheets, and poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) conductive polymers, enhancing the overall conductivity of the system. The nanoengineered surface chemistry allows for compatible direct assembly of bioreceptor molecules. CoVSense offers an inexpensive (<$2 kit) and fast/digital response (<10 min), measured using a customized hand-held reader (<$25), enabling data-driven outbreak management. The sensor shows 95% clinical sensitivity and 100% specificity (Ct<25), and overall sensitivity of 91% for combined symptomatic/asymptomatic cohort with wildtype SARS-CoV-2 or B.1.1.7 variant (N = 105, nasal/throat samples). The sensor correlates the N-protein levels to viral load, detecting high Ct values of ≈35, with no sample preparation steps, while outperforming the commercial rapid antigen tests. The current translational technology fills the gap in the workflow of rapid, point-of-care, and accurate diagnosis of COVID-19.

An image processing approach for blind mobility facilitated through visual intracortical stimulation.

This article presents an image processing approach dedicated for a blind mobility aid facilitated through visual intracortical electrical stimulation. The method examines a display framework based on the distances related to a scene. The distances of objects to the walker are measured using a size perspective method which uses only one camera without any occlusion effect. The method extracts the information of the closest object to the camera and transfers a sense of distance to a blind walker. The proposed image processing method can estimate the distances of objects within 7.5 m of the walker, and alert the presence of the closest object to the person. This new method offers the advantages of information reduction and scene understanding suitable for visual prosthesis.

A Hybrid Microfluidic Electronic Sensing Platform for Life Science Applications.

This paper presents a novel hybrid microfluidic electronic sensing platform, featuring an electronic sensor incorporated with a microfluidic structure for life science applications. This sensor with a large sensing area of 0.7 mm2 is implemented through a foundry process called Open-Gate Junction FET (OG-JFET). The proposed OG-JFET sensor with a back gate enables the charge by directly introducing the biological and chemical samples on the top of the device. This paper puts forward the design and implementation of a PDMS microfluidic structure integrated with an OG-JFET chip to direct the samples toward the sensing site. At the same time, the sensor's gain is controlled with a back gate electrical voltage. Herein, we demonstrate and discuss the functionality and applicability of the proposed sensing platform using a chemical solution with different pH values. Additionally, we introduce a mathematical model to describe the charge sensitivity of the OG-JFET sensor. Based on the results, the maximum value of transconductance gain of the sensor is ~1 mA/V at Vgs = 0, which is decreased to ~0.42 mA/V at Vgs = 1, all in Vds = 5. Furthermore, the variation of the back-gate voltage from 1.0 V to 0.0 V increases the sensitivity from ~40 mV/pH to ~55 mV/pH. As per the experimental and simulation results and discussions in this paper, the proposed hybrid microfluidic OG-JFET sensor is a reliable and high-precision measurement platform for various life science and industrial applications.

A High Dynamic Range Dual 8×16 Capacitive Sensor Array for Life Science Applications.

This paper presents a fully integrated complementary metal-oxide-semiconductor (CMOS) capacitive sensor array for life science applications. This sensing device consists of an array of 16 × 16 interdigitated electrodes (IDEs) integrated with a charge-based readout and multiplexing circuitries on the same chip. This chip was implemented in 0.35 µm AMS CMOS process. This sensing device has a wide input capacitance range (ICR) of about 100 fF and a resolution of 150 aF, and the capability of temporal, spatial, and dielectric sensing. It makes it possible to develop a low-cost, multimodal, calibration-free sensing platform for life science applications. Here, we demonstrate and discuss the functionality and applicability of the proposed sensing device by introducing various chemical solvents including ethanol, methanol, and pure water. The simulation and experimental results achieved in this work have taken us one step closer to a fully automated calibration-free multimodal capacitive sensing platform for high-throughput drug development and other purposes.